EP0242653B1 - Tpa-containing medical composition and use thereof - Google Patents
Tpa-containing medical composition and use thereof Download PDFInfo
- Publication number
- EP0242653B1 EP0242653B1 EP87104825A EP87104825A EP0242653B1 EP 0242653 B1 EP0242653 B1 EP 0242653B1 EP 87104825 A EP87104825 A EP 87104825A EP 87104825 A EP87104825 A EP 87104825A EP 0242653 B1 EP0242653 B1 EP 0242653B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tpa
- meglumine
- salt
- medical composition
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- This invention relates to a medical composition containing a tissue Plasminogen Activator (hereinafter called "tPA"). More specifically, the present invention relates to a tPA-containing medical composition with increased water-solubility of tPA, which comprises tPA in combination with meglumine or a salt thereof.
- tPA tissue Plasminogen Activator
- tPA acts on plasminogen in a living body to form plasmin and this plasmin destroys fibrin networks of thrombi to dissolve the same and tPA is hence a substance useful for the treatment of circulatory disorders caused by the formation of thrombi.
- tPA is a protein having an extremely low solubility in water. It is therefore very difficult to formulate tPA into a preparation which is administered after its dissolution in water, for example, into an injection. This is the greatest obstacle for the utilization of tPA in actual therapy.
- An object of this invention is therefore to provide a tPA-containing medical composition in which the water-solubility of tPA has been increased to a degree sufficient to permit the use of tPA in therapy.
- the present inventors carried out a variety of investigations with a view toward developing a technique to increase the solubility of tPA in water. As a result, it was found that a composition with improved water-solubility of tPA can be obtained by incorporating a diisocyanate-bound partial hydrolyzate of gelatin or arginine.
- Application for patents have already been filed on the basis of these findings (Japanese Patent Application Nos. 198,62g/1985 and 258,624/1985).
- tPA tissue Plasminogen Activator
- tPA may be one extracted from a natural source or one obtained from a microorganism prepared artificially by a bioengineering technique or a culture broth of animal cells. This invention is not limited to any specific origin for tPA.
- Meglumine i.eN-methyl-glucamine
- a salt thereof is employed in this invention.
- meglumine available in a salt form may be used directly as the salt of meglumine
- the salt of meglumine can be provided by incorporating both meglumine and an inorganic or organic acid in a composition of this invention.
- Illustrative examples of such a salt may include the hydrochloride, acetate, lactate, and gluconate.
- the medical composition of the present invention includes not only a solid or aqueous composition in which tPA and meglumine or a salt thereof are contained in combination but also a composition in such a form that tPA and meglumine or a salt thereof are individually packed, such as a vial containing lyophilized tPA and an ampule containing an aqueous solution of meglumine or a salt thereof and adapted for the dissolution of the lyophilized tPA, like an injection which can be formulated prior to its use.
- composition of the present invention may further contain auxiliary ingredients routinely employed in the formulation of dosable medical preparations, for example, one or more fillers, stabilizers, buffers and isotonic agents as needed.
- auxiliary ingredients routinely employed in the formulation of dosable medical preparations, for example, one or more fillers, stabilizers, buffers and isotonic agents as needed.
- composition of this invention may be carried out by a usual production method for a desired preparation form.
- a preparation method will next be described by way of example.
- An aqueous tPA solution is filled in portions in vials and is then lyophilized, thereby providing vials enclosing tPA-containing powder.
- an aqueous solution of the additive according to this invention is filled in portions in vials.
- One of the former vials is combined with one of the latter vials to provide a composition of this invention.
- solubility of tPA in water has been increased, whereby a high- concentration aqueous solution of tPA has been provided.
- a tPA-containing injection having a high potency can be provided.
- the solubility of tPA in water was 2100 U/mi (U is a potency unit) when meglumine was not added while the addition of meglumine increased it to 17,000 U/mi at 1%, 85,000 UlMi at 2% and 331,000 UlMi at 5% respectively, in which U/ml defines the solubility of tPA in water.
- U/mi U is a potency unit
- aqueous solution containing 10 g of meglumine and 3 g of mannitol was adjusted to pH 7 with hydrochloric acid. The total volume of the thus-adjusted solution was 100 mi. Ten million units of tPA were then added, whereby an aqueous solution containing 1,000,000 units of tPA was prepared under sterile conditions. One-ml portions of the aqueous solution were pipetted in vials, lyophilized and then sealed hermetically.
- ampules each containing 2 ml of distilled water for injection were prepared for dissolution.
- tPA powder Ten million units of tPA powder, which had been prepared under sterile conditions, and 3 g of sterile mannitol were mixed uniformly. In vials, the resultant mixture was filled and hermetically sealed in portions so that tPA was contained in an amount of 100,000 units per vial.
- an aqueous solution containing 10 g of meglumine was adjusted to pH 7 with lactic acid under sterile conditions.
- the total volume of the thus-adjusted aqueous solution was 200 mP.
- Ampules each containing 2 ml of the resultant aqueous solution were prepared for dissolution.
- tPA samples in an amount equivalent to 400,000 units were weighed separately in small testing tubes, to which there were respectively added 1 mP of aqueous solutions containing meglumine and adjusted to pH 7 respectively with various acids in an amount equivalent to the meglumine. After stirring, the resultant mixtures were separately centrifuged to obtain super natants as samples. Incidentally, the concentration of meglumine in each sample was 2%.
- aqueous solutions were prepared in exactly the same manner as the test samples except that in place of meglumine, sodium hydroxide was used in an amount equal in mole to the meglumine, thereby providing comparative samples.
- a predetermined amount of each sample was taken out and diluted with 0.1 M tris-HC£ buffer (pH 8; BSA was contained), followed by measurement of tPA activity (U/ml) by a fibrin plate.
- Results are summarized in Table 1. Numerical values given in Table 1 indicate tPA activities (U/ml). From Table 1, it is envisaged that the solubility of tPA is increased by an addition of a suitably-selected acid and is increased further to a significant extent by an addition of meglumine.
- Test samples were provided in the same manner as in Example 1 except that the concentration of meglumine was 1%, 2% and 5% and hydrochloric acid was employed singly as an acid, followed by measurement of their tPA activities (U/ml). Results are shown in Table 2. It is understood that the solubility of tPA increases as the concentration of meglumine increases.
Abstract
Description
- This invention relates to a medical composition containing a tissue Plasminogen Activator (hereinafter called "tPA"). More specifically, the present invention relates to a tPA-containing medical composition with increased water-solubility of tPA, which comprises tPA in combination with meglumine or a salt thereof.
- It is known that tPA acts on plasminogen in a living body to form plasmin and this plasmin destroys fibrin networks of thrombi to dissolve the same and tPA is hence a substance useful for the treatment of circulatory disorders caused by the formation of thrombi.
- However, tPA is a protein having an extremely low solubility in water. It is therefore very difficult to formulate tPA into a preparation which is administered after its dissolution in water, for example, into an injection. This is the greatest obstacle for the utilization of tPA in actual therapy.
- An object of this invention is therefore to provide a tPA-containing medical composition in which the water-solubility of tPA has been increased to a degree sufficient to permit the use of tPA in therapy.
- The present inventors carried out a variety of investigations with a view toward developing a technique to increase the solubility of tPA in water. As a result, it was found that a composition with improved water-solubility of tPA can be obtained by incorporating a diisocyanate-bound partial hydrolyzate of gelatin or arginine. Application for patents have already been filed on the basis of these findings (Japanese Patent Application Nos. 198,62g/1985 and 258,624/1985).
- The present inventors have proceeded with a further investigation. As a result, it has now been found that an addition of meglumine or a salt thereof to tPA can significantly increase the solubility of tPA further in water, leading to completion of this invention.
- In one aspect of this invention, there is thus provided a medical composition containing a tissue Plasminogen Activator (tPA), which comprises tPA in combination with meglumine or a salt thereof.
- The solubility of tPA has been increased to a considerable extent by the addition of meglumine or the salt thereof.
- The above and other objects, features and advantages of the present invention will become apparent from the following description and the appended claims.
- In the present invention, tPA may be one extracted from a natural source or one obtained from a microorganism prepared artificially by a bioengineering technique or a culture broth of animal cells. This invention is not limited to any specific origin for tPA.
- Meglumine (i.eN-methyl-glucamine) or a salt thereof is employed in this invention. Although meglumine available in a salt form may be used directly as the salt of meglumine, the salt of meglumine can be provided by incorporating both meglumine and an inorganic or organic acid in a composition of this invention. Illustrative examples of such a salt may include the hydrochloride, acetate, lactate, and gluconate.
- The medical composition of the present invention includes not only a solid or aqueous composition in which tPA and meglumine or a salt thereof are contained in combination but also a composition in such a form that tPA and meglumine or a salt thereof are individually packed, such as a vial containing lyophilized tPA and an ampule containing an aqueous solution of meglumine or a salt thereof and adapted for the dissolution of the lyophilized tPA, like an injection which can be formulated prior to its use.
- The composition of the present invention may further contain auxiliary ingredients routinely employed in the formulation of dosable medical preparations, for example, one or more fillers, stabilizers, buffers and isotonic agents as needed.
- The production of the composition of this invention may be carried out by a usual production method for a desired preparation form. A preparation method will next be described by way of example. An aqueous tPA solution is filled in portions in vials and is then lyophilized, thereby providing vials enclosing tPA-containing powder. On the side, an aqueous solution of the additive according to this invention is filled in portions in vials. One of the former vials is combined with one of the latter vials to provide a composition of this invention.
- It is an effect of this invention that the solubility of tPA in water has been increased, whereby a high- concentration aqueous solution of tPA has been provided. As a specific example, a tPA-containing injection having a high potency can be provided. According to experiments which will be described subsequently, the solubility of tPA in water was 2100 U/mi (U is a potency unit) when meglumine was not added while the addition of meglumine increased it to 17,000 U/mi at 1%, 85,000 UlMi at 2% and 331,000 UlMi at 5% respectively, in which U/ml defines the solubility of tPA in water. Namely, the significant effects of meglumine for the increase of the solubility of tPA in water are observed.
- The present invention will be described more specifically by the following Examples.
- An aqueous solution containing 10 g of meglumine and 3 g of mannitol was adjusted to pH 7 with hydrochloric acid. The total volume of the thus-adjusted solution was 100 mi. Ten million units of tPA were then added, whereby an aqueous solution containing 1,000,000 units of tPA was prepared under sterile conditions. One-ml portions of the aqueous solution were pipetted in vials, lyophilized and then sealed hermetically.
- Separately, ampules each containing 2 ml of distilled water for injection were prepared for dissolution.
- Ten million units of tPA powder, which had been prepared under sterile conditions, and 3 g of sterile mannitol were mixed uniformly. In vials, the resultant mixture was filled and hermetically sealed in portions so that tPA was contained in an amount of 100,000 units per vial.
- Separately, an aqueous solution containing 10 g of meglumine was adjusted to pH 7 with lactic acid under sterile conditions. The total volume of the thus-adjusted aqueous solution was 200 mP. Ampules each containing 2 ml of the resultant aqueous solution were prepared for dissolution.
- Advantages of this invention will next be described by the following Experiments.
- tPA samples in an amount equivalent to 400,000 units were weighed separately in small testing tubes, to which there were respectively added 1 mP of aqueous solutions containing meglumine and adjusted to pH 7 respectively with various acids in an amount equivalent to the meglumine. After stirring, the resultant mixtures were separately centrifuged to obtain super natants as samples. Incidentally, the concentration of meglumine in each sample was 2%. In addition, aqueous solutions were prepared in exactly the same manner as the test samples except that in place of meglumine, sodium hydroxide was used in an amount equal in mole to the meglumine, thereby providing comparative samples.
- A predetermined amount of each sample was taken out and diluted with 0.1 M tris-HC£ buffer (pH 8; BSA was contained), followed by measurement of tPA activity (U/mℓ) by a fibrin plate.
-
- Test samples were provided in the same manner as in Example 1 except that the concentration of meglumine was 1%, 2% and 5% and hydrochloric acid was employed singly as an acid, followed by measurement of their tPA activities (U/mℓ). Results are shown in Table 2. It is understood that the solubility of tPA increases as the concentration of meglumine increases.
Claims (7)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT87104825T ATE56147T1 (en) | 1986-04-02 | 1987-04-01 | MEDICINAL PREPARATION CONTAINING T-PA AND USE THEREOF. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61074370A JPH0678241B2 (en) | 1986-04-02 | 1986-04-02 | tPA pharmaceutical composition |
JP74370/86 | 1986-04-02 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0242653A1 EP0242653A1 (en) | 1987-10-28 |
EP0242653B1 true EP0242653B1 (en) | 1990-09-05 |
Family
ID=13545204
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP87104825A Expired - Lifetime EP0242653B1 (en) | 1986-04-02 | 1987-04-01 | Tpa-containing medical composition and use thereof |
Country Status (8)
Country | Link |
---|---|
US (1) | US4985245A (en) |
EP (1) | EP0242653B1 (en) |
JP (1) | JPH0678241B2 (en) |
AT (1) | ATE56147T1 (en) |
CA (1) | CA1289472C (en) |
DE (1) | DE3764697D1 (en) |
ES (1) | ES2031846T3 (en) |
GR (1) | GR3000751T3 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2520975B2 (en) * | 1989-09-21 | 1996-07-31 | 三井東圧化学株式会社 | Thrombolytic agent containing tissue plasminogen activator or its derivative |
DE3942142A1 (en) * | 1989-12-20 | 1991-06-27 | Boehringer Mannheim Gmbh | STABILIZATION OF GLYCOSYLATED T-PA |
DE3942143A1 (en) * | 1989-12-20 | 1991-06-27 | Boehringer Mannheim Gmbh | T-PA PRO STABILIZATION |
DE3942141A1 (en) * | 1989-12-20 | 1991-06-27 | Boehringer Mannheim Gmbh | K2P PRO STABILIZATION |
GB0007239D0 (en) * | 2000-03-24 | 2000-05-17 | Nycomed Imaging As | Use |
JP5468221B2 (en) * | 2008-08-04 | 2014-04-09 | 株式会社 メドレックス | Intravenous dispersion formulation of poorly soluble drugs |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5137343B2 (en) * | 1972-12-07 | 1976-10-15 | ||
US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
DE3584902D1 (en) * | 1984-02-29 | 1992-01-30 | Asahi Chemical Ind | AQUEOUS SOLUTION OF AN INCREASED CONCENTRATION OF TISSUE PLASMINOGEN ACTIVATOR AND PRODUCTION METHOD. |
-
1986
- 1986-04-02 JP JP61074370A patent/JPH0678241B2/en not_active Expired - Lifetime
-
1987
- 1987-04-01 EP EP87104825A patent/EP0242653B1/en not_active Expired - Lifetime
- 1987-04-01 AT AT87104825T patent/ATE56147T1/en not_active IP Right Cessation
- 1987-04-01 CA CA000533589A patent/CA1289472C/en not_active Expired - Fee Related
- 1987-04-01 DE DE8787104825T patent/DE3764697D1/en not_active Expired - Fee Related
- 1987-04-01 ES ES87104825T patent/ES2031846T3/en not_active Expired - Lifetime
-
1989
- 1989-11-03 US US07/430,949 patent/US4985245A/en not_active Expired - Fee Related
-
1990
- 1990-09-06 GR GR90400232T patent/GR3000751T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
ATE56147T1 (en) | 1990-09-15 |
EP0242653A1 (en) | 1987-10-28 |
JPS62234030A (en) | 1987-10-14 |
JPH0678241B2 (en) | 1994-10-05 |
ES2031846T3 (en) | 1996-07-16 |
US4985245A (en) | 1991-01-15 |
DE3764697D1 (en) | 1990-10-11 |
CA1289472C (en) | 1991-09-24 |
GR3000751T3 (en) | 1991-10-10 |
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